For the purpose of treating malignant tumors or viral diseases, various nucleic acid antimetabolites has been developed, and, cytarabine, gemcitabine, doxifluridine, azacitidine, decitabine, nelarabine and the like as antitumor agents (anticancer agents), and, zalcitabine, lamivudine and the like as antiviral agents are clinically used.
However, even though these nucleic acid antimetabolites exhibit strong in vitro activity, many of the antimetabolites cannot sufficiently exhibit the efficacy inherently possessed by the drugs, or need to be administered in large amounts, owing to their susceptibility to in vivo metabolization and excretion. For example, gemcitabine has a strong in vitro cell growth inhibitory activity which is comparable to that of anticancer agents such as paclitaxel or doxorubicin, while in clinical practice, gemcitabine needs to be administered at a high does of 1000 mg/m2 of the body surface area per administration. This is considered to be due to a decreased in vivo bioavailability owing to the metabolism/deactivation of the amino group at the 4-position of the base by a cytidine deaminase, which is a 2′-deoxycytidine metabolizing enzyme (see Non-Patent Document 1).
There are some cases where binding of a drug to a polymer results in an improvement in the pharmacokinetics in vivo, and thus to an enhancement of the therapeutic effect. Non-Patent Document 2 describes a high molecular weight derivative in which a polyglutamic acid having an average molecular weight of about 30,000 is conjugated with cytarabine. However, high molecular weight derivatives of drugs sometimes induce hypersensitivity due to immune responses, and in such cases, the high molecular weight derivatives as a drug cannot be administered repeatedly.
Patent Document 1 describes a high molecular weight derivative in which a cytidine derivative is bound to a polyethylene glycol, while Non-Patent Document 3 describes a high molecular weight derivative in which both ends of the chain of a polyethylene glycol are substituted with aspartic acid in a branched form, and cytarabine is bound thereto. Furthermore, Patent Document 6 describes a high molecular weight derivative having a structure in which the ends of a polyethylene glycol chain are branched by making use of amino acids, and each of the branches releases drug after being subjected to a benzyl elimination reaction. However, for all of these high molecular weight derivatives, the rate of hydrolysis in the blood plasma is not so much slowed, being several tens of hours at the most, and the high molecular weight derivatives themselves do not remain in vivo for a long time to release the included compounds over a long time. Also, since these high molecular weight derivatives have large differences between the rate of hydrolysis in phosphate buffered physiological saline (PBS) and the rate of hydrolysis in the blood plasma, and the hydrolysis reaction depends largely on the enzymes in vivo, it is possible that the therapeutic effects in the clinical practice may be greatly affected by the individual differences of patients.
Patent Document 2 describes that molecules in which a drug is bound to a block type polymer having a polyethylene glycol condensed with polyaspartic acid, form micelles and serve as a medicine. Furthermore, Patent Document 3 describes a polymer carrier which serves as a polymer vehicle, in which a hydrophobic substance is bound to a carboxyl group in the side chain of a block copolymer of a polyethylene glycol and a poly acidic amino acid. Furthermore, Patent Document 4 states a polymer in which an anticancerous substance is bound to a carboxyl group in the glutamic acid side chain of a block type polymer having a polyethylene glycol condensed with polyglutamic acid. However, there is no description with regard to these high molecular weight derivatives using a nucleic acid antimetabolite as the drug binding thereto.
Patent Document 5 states that water-soluble high molecular weight derivatives in which a carboxyl group of a polymer of polyethylene glycol and polycarboxylic acid is linked to a phenolic hydroxyl group of a phenolic camptothecin by ester condensation, are suitable for cancer chemotherapy. However, these polymers have a drug bound directly to a carboxyl group of a polymer of polyethylene glycol and polycarboxylic acid, and thus the drug is not linked via any linker. Also, there is no description with regard to a nucleic acid antimetabolite as the drug binding thereto.    Patent Document 1: Japanese Patent Application Laid-Open Publication (Kohyo) No. 2003-524028    Patent Document 2: Japanese Patent No. 2694923    Patent Document 3: Japanese Patent No. 3268913    Patent Document 4: Japanese Patent Application Laid-Open Publication (Kokai) No. 5-955    Patent Document 5: WO 2004/039869    Patent Document 6: Japanese Patent Application Laid-Open Publication (Kohyo) No. 2004-532289    Non-Patent Document 1: Cancer Science, Japanese Cancer Association, Vol. 95, pp. 105-111 (2004)    Non-Patent Document 2: Cancer Research, American Association for Cancer Research, Vol. 44, pp. 25-30 (1984)    Non-Patent Document 3: Journal of Controlled Release, Elsevier, Vol. 79, pp. 55-70 (2002)